Basel, Switzerland ( At the Advanced Prostate Cancer Consensus Conference (APCCC) 2019 Drs. Maha Hussain and Celestia Higano presented during the management of castration-resistant prostate cancer (CRPC) debate. Each clinician presented on one side of comparison regarding the treatment of non-metastatic (nmCRPC).  Dr. Higano presented on the “cons” of treating men with nmCRPC. The standard definition of nmCRPC is a serial rising PSA despite a castrate level of testosterone and no evidence of metastatic disease by conventional imaging (bone scan, CT chest, abdomen, pelvis). Inclusion for the recent trials only included men with high-risk nmCRPC, namely those with PSA doubling time < 10 months and PSA of 2 or greater. Importantly, Dr. Higano notes that the FDA approval label does not restrict the use of second-generation androgen antagonists to high-risk populations, even though lower-risk patients were not included.

The risk of bone metastases or death for men with nmCRPC is highly contingent on PSA doubling time, which has been shown in several studies. In an exploratory analysis of the denosumab nmCRPC trial assessment of MFS stratified by PSA doubling time, Smith et al.1 noted that in the placebo group, shorter bone MFS was observed as PSA doubling time decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased bone MFS by a median of 6.0 months for men with PSA doubling time of ≤ 10 (HR, 0.84; p = 0.042), 7.2 months for men with a PSA doubling time of ≤ 6 (HR, 0.77; p = 0.006), and 7.5 months among men with PSA doubling time ≤ 4 months (HR, 0.71; p=0.004), respectively. In a VA study of 441 men with nmCRPC, PSA doubling time < 3 months was associated with a nearly nine-fold increased risk of metastases (HR 8.63, 95% CI 5.07-14.7) and prostate cancer-specific mortality (HR 9.29, 95% CI 5.38-16.0) compared to patients with PSA doubling time ≥ 15 months.2 The median times to metastasis for patients with a PSA doubling time < 3 was 9 months, 3-8.9 was 19 months, 9-14.9 was 40 months, and ≥ 15 months was 50 months.

The MFS results noted in SPARTAN (median 40.5 months), PROSPER (median 36.6 months), and ARAMIS (median 40.4 months) are the first time this magnitude of difference has been reported. Even without overall survival (OS) data, difference in delaying time to metastasis is meaningful to patients, as long as they do not experience substantial toxicity. There is no head to head comparison data available for toxicities, which are most commonly fatigue, falls and fractures. Furthermore, there is no comparative data available for how these medications affect underlying comorbidities, specifically cardiovascular disease, hypertension, history of falls or seizures, frailty, and the impact of osteoporosis or osteopenia. Treating all patients with nmCRPC with second-generation AR targeted therapy could expose a significant number of men to longer durations of therapy and thus more potential for toxicity. The other important note is that especially in the US, the price of the medication can be upwards of $10,000/month.

As has been covered extensively at this meeting, the emergence and update of PSMA-PET imaging will identify more patients with nmCRPC who have early M1 CRPC. Based on this information, several questions arise: (i) Should the M1 nmCRPC patient be treated with therapy for mCRPC or should they be treated with second-generation androgen ablation (no prospective data)? (ii) Can PSMA PET imaging +/-PSA doubling time be used to identify patients who could delay systemic therapy and perhaps be treated with SBRT or other salvage approaches?

According to Dr. Higano, there are several cons associated with using second-line androgen receptor therapies for nmCRPC:

  • There is definitely toxicity at the individual patient level that we don’t yet understand: who will have it and how reversible is it?
  • Long-term effect on the natural history of mCRPC is unknown: will the more aggressive disease phenotype develop earlier in mCRPC due to longer exposure to androgen receptor therapies during nmCRPC?
  • Treating men with nmCRPC and longer PSA doubling time has a significant risk of doing more harm than good
  • The safe choice of agent and monitoring these agents require urologists to practice internal medicine
  • There can be significant financial toxicity for those who do not qualify for assistance programs ($10,000/month)
  • We will need a better understanding in the post-market setting about the toxicity of these agents relative to each other
  • Are there genetic, pharmacogenomics, or other biomarkers that can predict these patient-specific toxicities?
  • We will need a better understanding of the role of conventional imaging in concert with molecular imaging to better characterize the different subtypes of nmCRPC in clinical trials and to determine the role of salvage approaches guided by PSMA-PET in nmCRPC

Presented by: Celestia S. Higano, MD, FACP, Professor, Division of Medical Oncology, The University of Washington School of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA

Written by: Zachary Klaassen, MD, MSc–Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter:@zklaassen_md 


  1. Smith MR, Saad F, OudardS, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: Exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol 2013 Oct 20;31(30): 3800-3806.
  2. Howard LE, Moreira DM, De Hoedt A, et al. Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer. BJU Int 2017 Nov;120(5B): E80-E86.

Read the Opposing Debate:
Pro: – Maha Hussain, MD, FACP, FASCO